Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling psychiatric disorder that is notoriously difficult to treat. At some point in their lifetimes, 5-8% of men, 10-14% of women, and up to a quarter of combat veterans carry this diagnosis. Despite pharmacological and behavioral therapies, up to 30% of patients are still symptomatic 10 years after initial diagnosis. Recent advances in imaging have implicated changes in the limbic and autonomic corticostriatopallidothalamocortical (CSPTC) circuitry in the pathogenesis of this disease. Deep brain stimulation modulates CSPTC circuits in movement and other neuropsychiatric disorders. In this review, we discuss the salient clinical features and neurocircuitry of PTSD and propose a neuromodulation strategy for the disorder.

1.
American Psychiatric Association Task Force on DSM-IV: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, ed 4. Washington, American Psychiatric Association, 2000.
2.
Breslau N: Outcomes of posttraumatic stress disorder. J Clin Psychiatry 2001;62(suppl 17):55-59.
[PubMed]
3.
Vasterling JJ, Brailey K, Constans JI, Sutker PB: Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology 1998;12:125-133.
[PubMed]
4.
Vasterling JJ, Duke LM, Brailey K, Constans JI, Allain AN Jr, Sutker PB: Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology 2002;16:5-14.
[PubMed]
5.
Yehuda R: Post-traumatic stress disorder. N Engl J Med 2002;346:108-114.
[PubMed]
6.
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB: Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52:1048-1060.
[PubMed]
7.
Breslau N, Davis GC, Andreski P, Peterson E: Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry 1991;48:216-222.
[PubMed]
8.
Breslau N: The epidemiology of posttraumatic stress disorder: what is the extent of the problem? J Clin Psychiatry 2001;62(suppl 17):16-22.
[PubMed]
9.
Thomas JL, Wilk JE, Riviere LA, McGurk D, Castro CA, Hoge CW: Prevalence of mental health problems and functional impairment among active component and National Guard soldiers 3 and 12 months following combat in Iraq. Arch Gen Psychiatry 2010;67:614-623.
[PubMed]
10.
Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL: Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med 2004;351:13-22.
[PubMed]
11.
Highfill-McRoy RM, Larson GE, Booth-Kewley S, Garland CF: Psychiatric diagnoses and punishment for misconduct: the effects of PTSD in combat-deployed marines. BMC Psychiatry 2010;10:88.
[PubMed]
12.
Kehle SM, Reddy MK, Ferrier-Auerbach AG, Erbes CR, Arbisi PA, Polusny MA: Psychiatric diagnoses, comorbidity, and functioning in national guard troops deployed to Iraq. J Psychiatr Res 2011;45:126-132.
[PubMed]
13.
Kessler RC: Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry 2000;61(suppl 5):4-12, discussion pp 13-14.
[PubMed]
14.
Davidson JR, Hughes D, Blazer DG, George LK: Post-traumatic stress disorder in the community: an epidemiological study. Psychol Med 1991;21:713-721.
[PubMed]
15.
Hien DA, Jiang H, Campbell AN, Hu MC, Miele GM, Cohen LR, Brigham GS, Capstick C, Kulaga A, Robinson J, Suarez-Morales L, Nunes EV: Do treatment improvements in PTSD severity affect substance use outcomes? A secondary analysis from a randomized clinical trial in NIDA's Clinical Trials Network. Am J Psychiatry 2010;167:95-101.
[PubMed]
16.
Stein DJ, Ipser JC, Seedat S: Pharmacotherapy for post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2006:CD002795.
17.
Pae CU, Lim HK, Peindl K, Ajwani N, Serretti A, Patkar AA, Lee C: The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Int Clin Psychopharmacol 2008;23:1-8.
[PubMed]
18.
Van Etten ML, Taylor S: Comparative efficacy of treatments for post-traumatic stress disorder: a meta-analysis. Clin Psychol Psychother 1998;5:126-144.
19.
Bisson J, Andrew M: Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2007:CD003388.
20.
Institute of Medicine: Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, National Academies Press, 2008.
21.
Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, Geracioti TD Jr: Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 1999;156:585-588.
[PubMed]
22.
Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB, Charney DS: Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997;154:624-629.
[PubMed]
23.
Cook CJ: Stress induces CRF release in the paraventricular nucleus, and both CRF and GABA release in the amygdala. Physiol Behav 2004;82:751-762.
[PubMed]
24.
Yehuda R: Biology of posttraumatic stress disorder. J Clin Psychiatry 2001;62(suppl 17):41-46.
[PubMed]
25.
Yehuda R, Golier JA, Halligan SL, Meaney M, Bierer LM: The ACTH response to dexamethasone in PTSD. Am J Psychiatry 2004;161:1397-1403.
[PubMed]
26.
Yehuda R, Boisoneau D, Lowy MT, Giller EL Jr: Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry 1995;52:583-593.
[PubMed]
27.
Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ: Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acad Sci USA 2002;99:13908-13913.
[PubMed]
28.
Geracioti TD Jr., Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE Jr, Kasckow JW: CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry 2001;158:1227-1230.
[PubMed]
29.
Yehuda R, Siever LJ, Teicher MH, Levengood RA, Gerber DK, Schmeidler J, Yang RK: Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder. Biol Psychiatry 1998;44:56-63.
[PubMed]
30.
O'Donnell T, Hegadoren KM, Coupland NC: Noradrenergic mechanisms in the pathophysiology of post-traumatic stress disorder. Neuropsychobiology 2004;50:273-283.
[PubMed]
31.
Debiec J, LeDoux JE: Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann NY Acad Sci 2006;1071:521-524.
[PubMed]
32.
Debiec J, Ledoux JE: Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience 2004;129:267-272.
[PubMed]
33.
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE: Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 2003;24:151-180.
[PubMed]
34.
Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD: Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 2003;54:693-702.
[PubMed]
35.
Kopell BH, Greenberg BD: Anatomy and physiology of the basal ganglia: implications for DBS in psychiatry. Neurosci Biobehav Rev 2008;32:408-422.
[PubMed]
36.
Haber SN, Fudge JL, McFarland NR: Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci 2000;20:2369-2382.
[PubMed]
37.
Rezai AR, Machado AG, Deogaonkar M, Azmi H, Kubu C, Boulis NM: Surgery for movement disorders. Neurosurgery 2008;62(suppl 2):809-838, discussion pp 838-809.
[PubMed]
38.
Greenberg BD, Gabriels LA, Malone DA Jr, Rezai AR, Friehs GM, Okun MS, Shapira NA, Foote KD, Cosyns PR, Kubu CS, Malloy PF, Salloway SP, Giftakis JE, Rise MT, Machado AG, Baker KB, Stypulkowski PH, Goodman WK, Rasmussen SA, Nuttin BJ: Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 2010;15:64-79.
[PubMed]
39.
Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA: Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006;31:2384-2393.
[PubMed]
40.
Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B: Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet 1999;354:1526.
[PubMed]
41.
Van Laere K, Nuttin B, Gabriels L, Dupont P, Rasmussen S, Greenberg BD, Cosyns P: Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: a key role for the subgenual anterior cingulate and ventral striatum. J Nucl Med 2006;47:740-747.
[PubMed]
42.
Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH: Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2008;64:461-467.
[PubMed]
43.
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651-660.
[PubMed]
44.
Jimenez F, Velasco F, Salin-Pascual R, Velasco M, Nicolini H, Velasco AL, Castro G: Neuromodulation of the inferior thalamic peduncle for major depression and obsessive compulsive disorder. Acta Neurochir Suppl 2007;97:393-398.
[PubMed]
45.
Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, Klosterkotter J: The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive and anxiety disorders. J Chem Neuroanat 2003;26:293-299.
[PubMed]
46.
Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, du Montcel ST, Yelnik J, Chereau I, Arbus C, Raoul S, Aouizerate B, Damier P, Chabardes S, Czernecki V, Ardouin C, Krebs MO, Bardinet E, Chaynes P, Burbaud P, Cornu P, Derost P, Bougerol T, Bataille B, Mattei V, Dormont D, Devaux B, Verin M, Houeto JL, Pollak P, Benabid AL, Agid Y, Krack P, Millet B, Pelissolo A: Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 2008;359:2121-2134.
[PubMed]
47.
Gabriels L, Cosyns P, Nuttin B, Demeulemeester H, Gybels J: Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: psychopathological and neuropsychological outcome in three cases. Acta Psychiatr Scand 2003;107:275-282.
[PubMed]
48.
Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, Taylor SF, Martis B, Giordani B: Deep brain stimulation for refractory obsessive-compulsive disorder. Biol Psychiatry 2005;57:510-516.
[PubMed]
49.
Malone DA Jr., Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen SA, Machado AG, Kubu CS, Tyrka AR, Price LH, Stypulkowski PH, Giftakis JE, Rise MT, Malloy PF, Salloway SP, Greenberg BD: Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009;65:267-275.
[PubMed]
50.
Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E: The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 1995;15:4851-4867.
[PubMed]
51.
Smeets WJ, Marin O, Gonzalez A: Evolution of the basal ganglia: new perspectives through a comparative approach. J Anat 2000;196:501-517.
[PubMed]
52.
Oler JA, Birn RM, Patriat R, Fox AS, Shelton SE, Burghy CA, Stodola DE, Essex MJ, Davidson RJ, Kalin NH: Evidence for coordinated functional activity within the extended amygdala of non-human and human primates. Neuroimage 2012;61:1059-1066.
[PubMed]
53.
Heimer L: Basal forebrain in the context of schizophrenia. Brain Res Brain Res Rev 2000;31:205-235.
[PubMed]
54.
Ebeling U, von Cramon D: Topography of the uncinate fascicle and adjacent temporal fiber tracts. Acta Neurochir (Wien) 1992;115:143-148.
[PubMed]
55.
Baxter MG, Murray EA: The amygdala and reward. Nat Rev Neurosci 2002;3:563-573.
[PubMed]
56.
Rosenkranz JA, Grace AA: Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci 2002;22:324-337.
[PubMed]
57.
Delgado MR, Olsson A, Phelps EA: Extending animal models of fear conditioning to humans. Biol Psychol 2006;73:39-48.
[PubMed]
58.
Heimer L, de Olmos JS, Alheid GF, Pearson J, Sakamoto N, Shinoda K, Marksteiner J, Switzer RC 3rd: The human basal forebrain; in Bloom FE, Hokfelt T (eds): Handbook of Chemical Neuroanatomy. Amsterdam, Elsevier, 1999, pp 57-226.
59.
Walker DL, Toufexis DJ, Davis M: Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 2003;463:199-216.
[PubMed]
60.
Somerville LH, Whalen PJ, Kelley WM: Human bed nucleus of the stria terminalis indexes hypervigilant threat monitoring. Biol Psychiatry 2010;68:416-424.
[PubMed]
61.
Fox AS, Shelton SE, Oakes TR, Converse AK, Davidson RJ, Kalin NH: Orbitofrontal cortex lesions alter anxiety-related activity in the primate bed nucleus of stria terminalis. J Neurosci 2010;30:7023-7027.
[PubMed]
62.
Alheid GF: Extended amygdala and basal forebrain. Ann NY Acad Sci 2003;985:185-205.
[PubMed]
63.
De Olmos JS, Heimer L: The concepts of the ventral striatopallidal system and extended amygdala; in McGinty JF (ed): Advancing from the Ventral Striatum to the Extended Amygdala: Implications for Neuropsychiatry and Drug Abuse. New York, New York Academy of Sciences, 1999, pp 1-32.
64.
Martin LJ, Powers RE, Dellovade TL, Price DL: The bed nucleus-amygdala continuum in human and monkey. J Comp Neurol 1991;309:445-485.
[PubMed]
65.
McDonald AJ: Cell types and intrinsic connections of the amygdala; in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York, Wiley-Liss, 1992, pp 67-96.
66.
Lebow M, Neufeld-Cohen A, Kuperman Y, Tsoory M, Gil S, Chen A: Susceptibility to PTSD-like behavior is mediated by corticotropin-releasing factor receptor type 2 levels in the bed nucleus of the stria terminalis. J Neurosci 2012;32:6906-6916.
[PubMed]
67.
Choi DC, Furay AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP: Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs. J Neurosci 2007;27:2025-2034.
[PubMed]
68.
Croxson PL, Johansen-Berg H, Behrens TE, Robson MD, Pinsk MA, Gross CG, Richter W, Richter MC, Kastner S, Rushworth MF: Quantitative investigation of connections of the prefrontal cortex in the human and macaque using probabilistic diffusion tractography. J Neurosci 2005;25:8854-8866.
[PubMed]
69.
Kim MJ, Whalen PJ: The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J Neurosci 2009;29:11614-11618.
[PubMed]
70.
Shin LM: The amygdala in post-traumatic stress disorder; in Shiromani PJ, Keane TM, Ledoux JE (eds): Post-Traumatic Stress Disorder: Basic Science and Clinical Practice. New York, Humana Press, 2009, pp 319-334.
71.
Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, Koeppe RA, Fig LM: Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 1999;45:817-826.
[PubMed]
72.
Pissiota A, Frans O, Fernandez M, von Knorring L, Fischer H, Fredrikson M: Neurofunctional correlates of posttraumatic stress disorder: a pet symptom provocation study. Eur Arch Psychiatry Clin Neurosci 2002;252:68-75.
[PubMed]
73.
Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, Metzger LJ, Lasko NB, Orr SP, Pitman RK: A positron emission tomographic study of symptom provocation in PTSD. Ann NY Acad Sci 1997;821:521-523.
[PubMed]
74.
Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, Orr SP, Pitman RK: Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000;47:769-776.
[PubMed]
75.
Koenigs M, Huey ED, Raymont V, Cheon B, Solomon J, Wassermann EM, Grafman J: Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nat Neurosci 2008;11:232-237.
[PubMed]
76.
Quirk GJ, Likhtik E, Pelletier JG, Pare D: Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 2003;23:8800-8807.
[PubMed]
77.
Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, Peters PM, Metzger LJ, Dougherty DD, Cannistraro PA, Alpert NM, Fischman AJ, Pitman RK: Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry 2004;61:168-176.
[PubMed]
78.
Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL: Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 2009;66:1075-1082.
[PubMed]
79.
Shin LM, Lasko NB, Macklin ML, Karpf RD, Milad MR, Orr SP, Goetz JM, Fischman AJ, Rauch SL, Pitman RK: Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry 2009;66:1099-1107.
[PubMed]
80.
Sailer U, Robinson S, Fischmeister FP, Konig D, Oppenauer C, Lueger-Schuster B, Moser E, Kryspin-Exner I, Bauer H: Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder. Neuropsychologia 2008;46:2836-2844.
[PubMed]
81.
Vythilingam M, Nelson EE, Scaramozza M, Waldeck T, Hazlett G, Southwick SM, Pine DS, Drevets W, Charney DS, Ernst M: Reward circuitry in resilience to severe trauma: An fMRI investigation of resilient Special Forces soldiers. Psychiatry Res 2009;172:75-77.
[PubMed]
82.
Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ Jr, Rothlind J, Sagher O, Moy C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ: Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med 2010;362:2077-2091.
[PubMed]
83.
Knight G: The orbital cortex as an objective in the surgical treatment of mental illness. The results of 450 cases of open operation and the development of the stereotactic approach. Br J Surg 1964;51:114-124.
[PubMed]
84.
Langevin JP, De Salles AA, Kosoyan HP, Krahl SE: Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res 2010;44:1241-1245.
[PubMed]
85.
Heath RG, Monroe RR, Mickle WA: Stimulation of the amygdaloid nucleus in a schizophrenic patient. Am J Psychiatry 1955;111:862-863.
[PubMed]
86.
Mpakopoulou M, Gatos H, Brotis A, Paterakis KN, Fountas KN: Stereotactic amygdalotomy in the management of severe aggressive behavioral disorders. Neurosurg Focus 2008;25:E6.
[PubMed]
87.
Narabayashi H, Nagao T, Saito Y, Yoshida M, Nagahata M: Stereotaxic amygdalotomy for behavior disorders. Arch Neurol 1963;9:1-16.
[PubMed]
88.
Lee GP, Bechara A, Adolphs R, Arena J, Meador KJ, Loring DW, Smith JR: Clinical and physiological effects of stereotaxic bilateral amygdalotomy for intractable aggression. J Neuropsychiatry Clin Neurosci 1998;10:413-420.
[PubMed]
89.
Jobst BC, Darcey TM, Thadani VM, Roberts DW: Brain stimulation for the treatment of epilepsy. Epilepsia 2010;51(suppl 3):88-92.
[PubMed]
90.
Arnsten AF: Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009;10:410-422.
[PubMed]
You do not currently have access to this content.